Comparative Studies of Three 68Ga-Labeled [Des-Arg10]Kallidin Derivatives for Imaging Bradykinin B1 Receptor Expression with PET

Kuo-Shyan Lin; Guillaume Amouroux; Jinhe Pan; Zhengxing Zhang; Silvia Jenni; Joseph Lau; Zhibo Liu; Navjit Hundal-Jabal; Nadine Colpo; François Bénard

doi:10.2967/jnumed.114.152132

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FIGURE 1.
Chemical structures of P03034, P04158, and Z02090. Unnatural amino acids in receptor-binding domain are shown in brown.
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FIGURE 2.
Representative displacement curves of [³H]-[Leu⁹,des-Arg¹⁰]Kallidin by P03034, P04158, and Z02090.
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FIGURE 3.
PET/CT images of ⁶⁸Ga-labeled P03034, P04158, and Z02090 in mice bearing both B1R+ (yellow arrows) and B1R− (red arrows) tumors without (upper) and with (lower) coinjection of cold standard (100 μg).
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FIGURE 4.
Difference on uptake of ⁶⁸Ga-labeled B1R-targeting tracers between B1R+ and B1R− tumors in mice in control (A) and blocked (B) groups. *P < 0.05. ***P < 0.001.

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TABLE 1

Amino Acid Sequences and B1R Binding Affinities of BK and Related Peptides

Peptide	Radiolabel complex–linker	Sequence											Ki (nM)	Reference
BK				Arg	Pro	Pro	Gly	Phe	Ser	Pro	Phe	Arg	5.7^*	29
Kallidin			Lys 1	Arg 2	Pro 3	Pro 4	Gly 5	Phe 6	Ser 7	Pro 8	Phe 9	Arg 10	7.4^*	29
[des-Arg¹⁰]kallidin			Lys	Arg	Pro	Pro	Gly	Phe	Ser	Pro	Phe		9.7^*	29
[Leu⁹,des-Arg¹⁰]kallidin			Lys	Arg	Pro	Pro	Gly	Phe	Ser	Pro	Leu		8.9^†	29
P03083	Ga-DOTA-Ahx		Lys	Arg	Pro	Pro	Gly	Phe	Ser	Pro	Leu		2.6 ± 0.7	23
P03034	Ga-DOTA-dPEG2		Lys	Arg	Pro	Hyp	Gly	Cha	Ser	Pro	Leu		16.0 ± 1.9	23
B9858		Lys	Lys	Arg	Pro	Hyp	Gly	IgI	Ser	D-IgI	Oic		10.1^†	24
B9958		Lys	Lys	Arg	Pro	Hyp	Gly	Cpg	Ser	D-Tic	Cpg		0.089	25
P04158	Ga-DOTA-dPEG2	Lys	Lys	Arg	Pro	Hyp	Gly	IgI	Ser	D-IgI	Oic		1.5 ± 1.9	—
Z02090	Ga-DOTA-dPEG2	Lys	Lys	Arg	Pro	Hyp	Gly	Cpg	Ser	D-Tic	Cpg		1.1 ± 0.8	—

↵* pEC₅₀ (EC₅₀ is the concentration of a drug needed to induce its half-maximal response).
↵† pIC₅₀ (IC₅₀ is the concentration of an inhibitor needed to reduce response by half).

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TABLE 2

Radiolabeling, LogD_7.4, and Plasma Stability Data of ⁶⁸Ga-Labeled [Des-Arg¹⁰]Kallidin Derivatives

						Plasma stability (% intact) (min)
Tracer	Overall charge	Radiochemical yield (%, decay-corrected)	Radiochemical purity (%)	Specific activity (GBq/μmol, n ≥ 3)	LogD_7.4 (n = 3)	5	15	30	60
⁶⁸Ga-P03034	+1	69 ± 8 (n = 7)	>99	222 ± 37	−2.76 ± 0.11	99	97	94	91
⁶⁸Ga-P04158	+2	76 ± 7 (n = 8)	>99	89 ± 22	−2.50 ± 0.16	99	97	96	94
⁶⁸Ga-Z02090	+2	67 ± 10 (n = 3)	>99	100 ± 33	−2.71 ± 0.12	93	91	88	81

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TABLE 3

Biodistribution Data of ⁶⁸Ga-Labeled [Des-Arg¹⁰]Kallidin Derivatives at 1 Hour After Injection in Tumor-Bearing Mice

	⁶⁸Ga-P03034		⁶⁸Ga-P04158		⁶⁸Ga-Z02090
Tissue (%ID/g)	Control (n = 5)	Blocked (n = 4)	Control (n = 5)	Blocked (n = 4)	Control (n = 5)	Blocked (n = 4)
Blood	0.46 ± 0.34	0.23 ± 0.06	1.12 ± 0.37	1.53 ± 0.54	0.50 ± 0.13	0.62 ± 0.09
Fat	0.11 ± 0.10	0.08 ± 0.08	0.18 ± 0.04	0.20 ± 0.12	0.07 ± 0.02	0.09 ± 0.00
Testes	0.16 ± 0.10	0.12 ± 0.11	0.31 ± 0.08	0.34 ± 0.12	0.15 ± 0.06	0.20 ± 0.04
Large intestine	0.19 ± 0.12	0.14 ± 0.02	0.41 ± 0.15	0.46 ± 0.17	0.20 ± 0.05	0.20 ± 0.03
Small intestine	0.22 ± 0.26	0.13 ± 0.07	0.47 ± 0.05	0.62 ± 0.18	0.24 ± 0.07	0.45 ± 0.17
Spleen	0.23 ± 0.17	0.11 ± 0.03	0.46 ± 0.12	0.51 ± 0.13	0.31 ± 0.10	0.34 ± 0.05
Liver	0.18 ± 0.10	0.14 ± 0.05	0.72 ± 0.11	0.79 ± 0.18	0.32 ± 0.07	0.29 ± 0.03
Pancreas	0.07 ± 0.08	0.06 ± 0.01	0.26 ± 0.03	0.30 ± 0.12	0.11 ± 0.02	0.13 ± 0.02
Adrenal glands	0.15 ± 0.16	0.15 ± 0.17	1.19 ± 0.78	0.68 ± 0.44	0.37 ± 0.19	0.27 ± 0.09
Kidney	4.50 ± 2.17	3.19 ± 0.72	69.2 ± 7.39	52.7 ± 2.85	50.1 ± 9.68	47.9 ± 7.78
Lungs	0.53 ± 0.38	0.20 ± 0.05	0.89 ± 0.17	1.27 ± 0.40	0.48 ± 0.09	0.52 ± 0.04
Heart	0.15 ± 0.07	0.09 ± 0.02	0.52 ± 0.13	0.59 ± 0.22	0.21 ± 0.06	0.27 ± 0.04
B1R− tumor	0.36 ± 0.09	0.25 ± 0.09	0.61 ± 0.21	0.67 ± 0.21	0.53 ± 0.18	0.45 ± 0.11
B1R+ tumor	2.17 ± 0.49	0.41 ± 0.08*	19.6 ± 4.50	1.44 ± 0.12*	14.4 ± 1.63	0.85 ± 0.17*
Muscle	0.13 ± 0.13	0.06 ± 0.01	0.30 ± 0.05	0.45 ± 0.26	0.12 ± 0.04	0.13 ± 0.02
Bone	0.10 ± 0.10	0.09 ± 0.03	0.45 ± 0.03	0.50 ± 0.17	0.22 ± 0.09	0.26 ± 0.07
Brain	0.01 ± 0.01	0.02 ± 0.02	0.03 ± 0.01	0.03 ± 0.01	0.01 ± 0.01	0.02 ± 0.01
B1R+ tumor to B1R− tumor	6.23 ± 1.69	1.85 ± 0.88^†	34.5 ± 10.5	2.33 ± 0.76*	29.3 ± 9.68	2.04 ± 0.79*
B1R+ tumor to blood	5.72 ± 2.20	1.92 ± 0.58^†	19.2 ± 8.21	1.05 ± 0.43^†	29.9 ± 5.58	1.37 ± 0.23*
B1R+ tumor to muscle	25.5 ± 13.1	6.61 ± 1.54^‡	66.1 ± 17.0	4.36 ± 2.96*	124 ± 28.1	6.85 ± 1.59*
B1R+ tumor to liver	14.6 ± 6.16	3.10 ± 1.05^†	26.9 ± 2.93	1.90 ± 0.51*	45.6 ± 5.86	3.09 ± 0.40*
B1R+ tumor to kidney	0.54 ± 0.18	0.13 ± 0.04^†	0.28 ± 0.05	0.03 ± 0.00*	0.30 ± 0.07	0.02 ± 0.00*